IL‐18 is produced by prostate cancer cells and secreted in response to interferons

Abstract

Key words: IL-18; caspase-1; prostate cancer; prognosis; IFN-␥; IFN-␣IL-18 was first identified as an IGIF based on its ability to induce high levels of IFN-␥ secretion by both NK cells and Th1 clones. 1,2 IL-18 belongs to the IL-1 family, 3 lacks a signal sequence 2 and is processed into an 18 kDa mature form by caspase-1. 4 It is mainly produced by macrophages and dendritic cells. However, we and others have shown that IL-18 is also synthesized by nonimmune cells. 5 IL-18 potentiates IL-12-induced Th1 development 6,7 and plays an important role in T-cell proliferation. 2 In addition, it enhances FasL-mediated cytotoxicity of NK cells and Th1 cells 8,9 and has proinflammatory properties by inducing chemotactic molecules for macrophages, polymorphonuclear neutrophils and inflammatory cytokines such as TNF-␣ or IL-1␤. 10 -12 Murine models have demonstrated the antitumor activity of IL-18, either by systemic administration 13,14 or in tumors genetically modified to constitutively express IL-18. 15 Antitumor effects are mediated by IL-18-induced IFN-␥, NK cells and T CD4 ϩ Fas-dependent cytotoxicity. [13][14][15][16] In vitro, IL-18 added to cultures of tumor cells, NK cells, dendritic cells and T cells induces tumor cell death by enhancing NK cell cytotoxicity, which activates dendritic cells to promote a specific CTL response. 17 This could position IL-18 as an important bridge between innate and adaptive antitumor immune responses. Some antitumor effects of IL-18 may also be mediated via nonimmunologic mechanisms as IL-18 has antiangiogenic properties in vitro and immunohistochemistry studies have revealed hypovascularization of IL-18-treated tumors. 15,18 Little is known about the in vivo presence of IL-18 in human tumors. In a previous study, we observed that IL-18 protein was expressed at various levels in colon cancers and that loss of transcripts at the tumor site of the 2 downstream targets of IL-18, i.e., IFN-␥ and FasL, was associated with the concomitant presence of distant metastases. 19 These results suggested a role of IL-18 in the control of tumor spreading in humans, in line with the antitumor properties of IL-18 observed in murine models.Research in prostate cancer has focused on the role of IFN-␥ in tumor progression. In vitro, IFN-␥ causes cycle arrest of prostate tumor cell lines, induces the cyclin-dependent kinase inhibitor p21 WAF1 , downregulates neu/HER-2 20 and decreases the metastatic potential of some prostate cancer cell lines. 21 IFN-␥ is produced by stromal and epithelial cells in normal prostate and prostate cancers, 22 and analysis of the transcriptional profile of prostate cancers by Affymetrix (Santa Clara, CA) Genechip technology has shown that about 30% of malignant tumors present downmodulation of IFN-␥-inducible molecules. 23 This may indicate modulation of IFN-␥ in tumors, but no information is available about the existence of the IFN-␥-inducing cytokine IL-18 in normal prostate and prostate cancers. We therefore investigated the IL-18 status of prostate cancers and its as...

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil: Implications for anti-tumor immune response

“…23 This effect, together with a role of IL-18 in effective priming of CTL and Th1 cells, appears to be an important factor for the effective elimination of tumor cells. 8 The wide range of IL-18 expression in epithelial neoplasia, including human colon carcinoma, 34 malignant skin tumors, 43 ovarian carcinoma, 44 squamous cell carcinoma cells, 45 prostate cancer cells 46 and, head and neck cancer 47 raises the issue whether drug-induced IL-18 processing is relevant to these tumor entities as well. As in pancreatic carcinoma (this study), the cytokine is predominantly produced intracellularly and secreted by these epithelial tumor cells as the unprocessed 24-kDa inactive precursor requiring proteolytic processing for activation.…”

“…Thus, coexpression and the dynamics of activation of different Caspases will determine the extent to which IL-18 is processed in epithelial tumor cells. In several types of tumors expressing IL-18 34,44,46 the lack of mature IL-18 has been ascribed to the absence of Caspase-1 gene expression. This does not appear to be the case in pancreatic carcinoma, since we observed high level expression of Caspase-1 mRNA and protein in the majority of tumors included in this study.…”

TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance

“…[24][25][26] IL-18 is crucially involved in tissue homeostasis. [27][28][29] In vivo studies have shown IL-18 expression during late stages of tumorigenesis in tumor tissues and the serum of patients with various types of cancer 30,31 together with an immunoablative role of natural killer (NK) cells. 32 Various epithelial cells express NLRs 33,34 ; however, the role of NLRs in the activation of inflammasomes within tissue-derived malignant and infected cells, as well as their direct role in controlling effector functions of intraepithelial lymphocytes (IEL), remains to be defined.…”

Effect of IL-18 gene promoter polymorphisms on prostate cancer occurrence and prognosis in Han Chinese population

“…It was reported that by acting as an autocrine or paracrine factor, IL-18 could be produced and secreted by prostate cancer cells in response to interferon (Lebel-Binay et al, 2003). Tse et al (2011) used murine animal models of prostate cancer to investigate this mechanism and found that local expression of IL-18 in prostate cancer tissue might inhibit the development of this tumor through innate and adaptive immune pathways.…”

“…IL-18 expression in prostate cancer is also related to tumor outcome such as pathologic stage J.M. Liu et al ( Lebel-Binay et al, 2003) and the transition from androgen-responsive to hormone-refractory prostate cancer (Desai et al, 2004).…”